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Uraemic toxins impair skeletal muscle regeneration by inhibiting myoblast proliferation, reducing myogenic differentiation, and promoting muscular fibrosis

Elena Alcalde‑Estévez, Patricia Sosa, Ana Asenjo‑Bueno, Patricia Plaza, Gemma Olmos, Manuel Naves‑Díaz, Diego Rodríguez‑Puyol, Susana López‑Ongil & María P. Ruiz‑Torres, are the authors of an article recently published in the Journal Scientific Reports, of Nature Research, ·mentioning the collaboration in the investigation of the ICTS “NANBIOSIS” U17 Confocal Microscopy Service of CIBER-BNN and the University of Alcalá.

Uremic toxins (UT) increase in the serum in parallel with a decrease in the glomerular filtration rate and the development of sarcopenia in patients with chronic kidney disease (CKD).

This study analyses the role of UTs in sarcopenia associated with CKD in different stages of the disease.

Immunofluorescence and senescence assays were visualised using a Leica SP5 confocal microscope (Leica Microsystems, Wetzlar, Germany), through the Unit 17 Confocal Microscopy Service of the ICTS ‘NANBIOSIS’)

Through confocal microscopy studies in C2C12 cells (myoblasts), the role of high concentrations of UT in different mechanisms involved in the biology of skeletal muscle cells was observed. It was observed that they did not induce senescence (associated with beta-galactatosidase activity), but they did decrease the proliferative capacity of myoblasts, preventing the cells from entering the mitosis phase in a step prior to the condensation of chromosomes. Also, through confocal microscopy studies, it was determined that low concentrations of UT hindered myogenic differentiation of myoblasts in culture and promoted the expression of fibrosis markers” – explains Isabel Trabado, Technical Coordinator of NANBIOSIS U17

Article of reference: Alcalde-Estévez, E., Sosa, P., Asenjo-Bueno, A. et al. Uraemic toxins impair skeletal muscle regeneration by inhibiting myoblast proliferation, reducing myogenic differentiation, and promoting muscular fibrosis. Sci Rep 11512 (2021). [DOI] 

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Elena Aznar Gimeno (NANBIOSIS U26) leads a CIBER-BBN transfer project.

The CIBER-BBN transfer program, with its call for transfer projects, has selected two projects for next year with the aim of promoting the transfer of scientific or technological results, derived from the research carried out by the CIBER-BBN groups, to the industrial sector.

One of these projects selected is directed by Elena Aznar Gimeno, researcher from the group led by Ramon Martínez Máñez at the IDM-Polytechnic University of Valencia, together with an external group led by Javier Pemán García, from the La Fe Health Research Institute From Valencia.

The project has been jointly financed by CIBER-BBN and a company interested in the technology and will count with the participation of NANBIOSIS Unit 26 Biomedical Applications II

The CIBER-BBN call for transfer projects, which is now in its eighth edition, has financed fourteen projects with as many companies since its creation.

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Collaboration of two NANBIOSIS units in the Valorisation Project “ADVERT”

The Project ADVERT (Advanced Extracellular Vesicles for Enzyme Replacement Therapy) is a research valorisation project recently granted by CIBER.

The project pursues to advance the development of extracellular vesicles as treatments for lysosomal diseases, specially to bring new therapies to treat FABRY disease.

The ADVERT Project will count on the active particpation of two NANBIOSIS units of CIBER-BBN:

The project will be financed with € 20,000.

The CIBER-BBN transfer program

The CIBER-BBN transfer program through its call for transfer and valorization projects has been designed to promote the transfer to the industrial sector of scientific or technological results derived from the research carried out by the CIBER-BBN groups. These transfer projects will make it possible to support the commercialization of said results, since there is a company that has shown interest in them and that provides at least, the same financing than CIBER-BBN for their achievement.

The call for valorisation projects is in its fourth edition, having already financed a total of fourteen projects.

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Participation of NANBIOSIS U25 in the Valorisation Project MR-INITIATE

The Unit 25 of the ICTS NANBIOSIS will be enrolled, through its scientific coordinator Ana Paula Candiota, in a research valorisation project recently granted by CIBER: “Noninvasive MR-based ImagiNg of Immune sysTem action during glIoblastomA TreatmEnt (MR-INITIATE)”

Such project has the aim to increase the TRL of therapy response follow-up methods in glioblastomas, using technological approaches performed at  U25 of NANBIOSIS NMR: Biomedical Applications I

The project will be financed with € 20,000.

The CIBER-BBN transfer program

The CIBER-BBN transfer program through its call for transfer and valorization projects has been designed to promote the transfer to the industrial sector of scientific or technological results derived from the research carried out by the CIBER-BBN groups. These transfer projects will make it possible to support the commercialization of said results, since there is a company that has shown interest in them and that provides at least, the same financing than CIBER-BBN for their achievement.

The call for valorization projects is in its fourth edition, having already financed a total of fourteen projects.

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Launching the Preliminary Market Consultation Webinar of the TREMIRS Project: Minimally Invasive Robotic Surgical Systems

Cáceres, April 15th, 2021

The CCMIJU, as a beneficiary of the Innovative Public Procurement Program of the Ministerio de Ciencia e Innovación, through the project “Minimally Invasive Robotic Surgery Systems” (TREMIRS), will invest € 7,345,300 in the development of innovative solutions in surgical robotics to improve services provided to the patient, the surgeon’s ergonomics and offer greater benefits to the surgical team, thus achieving an increase in the quality of healthcare.

This ambitious challenge, 80% co-funded by the European Regional Development Fund under the Programa Operativo Plurirregional de España (POPE) 2014-2020 and by the Consejería de Economía, Ciencia y Agenda Digital de la Junta de Extremadura, will last three years and will develop two innovative solutions in the field of surgical robotics, one focused on laparoscopic robotic surgery and the other on microsurgical robotics.

The first solution will facilitate new surgical approaches, provide improvements in surgeon ergonomics, advances in surgical assistance systems, and new portable training tools. The second will implement robotic micro-instruments for soft tissue manipulation and for performing microsurgical techniques such as anastomosis, suturing and ligation on small anatomical structures such as blood vessels, nerves and lymphatic ducts.

The development of both platforms will provide the National Health System and the Extremadura Health Service new equipment that is not currently available on the market and that will improve the quality of patient services and surgical results.

The project is currently in the preliminary market consultation phase as a prior action to the Innovative Public Procurement procedure for the aforementioned solutions. The purpose of this consultation is to obtain information about innovative solutions that respond to the challenges of the project through technologies that exceed the benefits of the existing ones. The results of this consultation will allow us to define the technical and functional specifications of the solutions to be achieved with a subsequent public procurement process.

You can find more information about the project and the preliminary market consultation at the free webinar on April 21, 2021 at 10:00 am.

Registration: https://www.ayming.es/insights-y-noticias/eventos/jornada-presentacion-consulta-preliminar-mercado-proyecto-tremirs-sistemas-cirugia-robotica-minima-invasion/

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New organ-on-chip models provide new information for targeted treatments in personalised medicine

Xavi Illa, Gemma Gabriel, Mar Alvarez and Rosa Villa, researchers of NANBIOSIS ICTS U8 Micro– Nano Technology Unit (from CIBER-BBN and the IMB-CNM-CSIC). are co-authors of two reviews that summarise the latest efforts in organ-on-chip technologies to emulate in vitro microfluidic systems. These devices are an opportunity to evolve the fields of biofabrication and sensing technology.

Organ-on-chip (OOC) technology has been an efficient tool in modern research to substitute laboratory mice and simulate tissue and organ-level physiology and function. In particular, these in vitro devices have been extensively applied to model the intestine, enhancing the research community’s knowledge about intestinal physiology and pathophysiology in order to develop targeted therapies for a more precise and personalised treatment of intestinal diseases.

Now, a review published in Biosensors & Bioelectronics signed by researchers of NANBIOSIS ICTS U8 Micro– Nano Technology Unit, collects information about the intestine models and highlights the necessity to integrate sensors into these in vitro models to shine light on the pathological mechanisms of intestinal disorders at their early stage. The detection of a disease at its early state would allow more efficient treatments and a better prognosis, reducing costs and enhancing the quality of life of the patients.

Last years’ research has had a significant impact in these complex microfluidic systems, though there is still a long way to go to increase biosensors capacity in their operations.

The potential of the OOC technology is enormous. OOC technology may provide a true precision medicine, allowing the use of the patients’ own cells for performing drugs screening before treating the patient“, -explains Mar Álvarez– “To that end, we believe that the integration of sensors into this platforms is mandatory to understand and evaluate the functioning of the organ in real time, providing information that may be used for in-situ decision making”.

Hydrogel microfluidic platforms to improve the predictive capacities of the in vitro models

Another review article published by theese researchers in Applied Materials & Interfaces tackles the progress made in tissue barrier models, as they have a crucial role in regulating organ homeostasis. Current microfluidic systems do not properly mimic cells’ interaction, so recent developments have included biomaterials, such as hydrogels, to emulate these boundaries between tissues and external environment. A hydrogel acts as a microenvironment of the cell and it permits cell culture.

The hydrogel mimics the real cell microenvironment, providing the mechanical cues needed to reproduce the proper organ physiology and function“, Mar Álvarez adds.

Recent developments in the fields of biofabrication show that hydrogels are able to mimic and change the tissue properties and dynamics, thus enabling an in vivo recreation for its reparation.

Articles of reference

Marrero D, Pujol-Vila F, Vera D, Gabriel G, Illa X,  Elizalde-Torrent A, Alvarez M, Villa R, Gut-on-a-chip: Mimicking and monitoring the human intestine. Biosensors and Bioelectronics. Volume 181, 1 June 2021, 113156. DOI https://doi.org/10.1021/acsami.0c21573

Vera D, García-Díaz M, Torras N, Alvarez M, Villa R, Martínez E. Engineering Tissue Barrier Models on Hydrogel Microfluidic Platforms, CS Appl. Mater. Interfaces 2021, 13, 12, 13920–13933 DOI https://doi.org/10.1016/j.bios.2021.113156

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Toxicity evaluation on non-target organisms with the collaboration of NANBIOSIS U17 Confocal microscopy

Sara Jiménez-Jiménez, Georgiana Amariei, Karina Boltes, María Ángeles García and María Luisa Marina have recently published an article in the Journal of Chromatography A, ·mentioning the collaboration in the investigation of the ICTS “NANBIOSIS” U17 Confocal Microscopy Service of CIBER-BNN and the University of Alcalá.

The echocytotoxicity of racemic panthenol and dexpanthenol at different concentrations and exposure times in Spirodela polyrhiza has been studied using NANBIOSIS U17 Confocal Microscopy Service

“Panthenol (racemic mixture) and its isomer dexpanthenol have been classified as toxic for the aquatic environment by the European Regulation (EC 1272/2008). These studies are based on the natural emission (autofluorescence) of chlorophyll in different parts of the aquatic plant Spirodela polyrhiza (root, shoot and leaf). The estimation of the IC50 for each one of the compounds concludes different behavior of the compounds in the different parts of the plant, showing a higher toxicity for the racemic mixture panthenol”, explains Isabel Trabado, Technical Coordinator of NANBIOSIS U17

Article of reference:

Sara Jiménez-Jiménez, Georgiana Amariei, Karina Boltes, María Ángeles García and María Luisa Marina. Enantiomeric separation of panthenol by Capillary Electrophoresis. Analysis of commercial formulations and toxicity evaluation on non-target organisms. Journal of Chromatography A 1639 (2021) 461919. [DOI]

Financial support:

Spanish Ministry of Science and Innovation (research project PID2019-104913GB-I00). Dirección General de Universidades e Investigación de la Comunidad de Madrid (Spain), REMTAVARES (project S2018/EMT-4341). University of Alcalá for research projects CCG19/CC-068 and CCG19/IA-050, and for G.A.’s post-doctoral contract. Spanish Ministry of Science, Innovation and Universities for S.J.J.’s FPU pre-doctoral contract.

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A GLOBAL VISION OF THE COVID-19 PANDEMIC by CSIC

A report from the Spanish National Research Council (CSIC) collects in open access the results of a year of research on SARS-CoV-2. The book ‘A global vision of the COVID-19 pandemic’ shows the responses and solutions obtained by the 300 research teams of the CSIC Global Health Platform. The Institute for Advanced Chemistry of Catalonia (IQAC-CSIC) has participated in the preparation of the chapter ‘Actions in containment and diagnosis’:

Visit CSIC website to read the full news.

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A new european infrastructure will facilitate the transfer of nano-pharmaceuticals from the lab to the clinic

Launch of the cross-european PHOENIX project, which will provide a new infrastructure available to research laboratories, SMEs and start-ups to facilitate the transfer of nano-pharmaceuticals from the laboratory to clinical practice. PHOENIX will have a duration of 4 years and a total budget of 14.45 million euros. Two CSIC Institutes, ICMAB (CSIC) and INMA (CSIC-UNIZAR), and one CSIC spin-off, Nanomol Technologies, participate in the project, will count with the expertise of NANBIOSIS unit 6 (from CIBER-BBN and ICMAB-CSIC), led by Nora Ventosa.

PHOENIX is an innovation project funded by EU’s Horizon2020 Framework Programme aimed to provide services for the development, characterization, testing, safety assessment, scale-up, good-manufacturing-practice (GMPs) production and commercialization of nano-pharmaceuticals from the lab to the market, making them available to SMEs, startups, research laboratories and interested users.

A total of 11 partners from academia and industry located all across Europe have joined forces to create this “Open Innovation Test Bed” for nano-pharmaceuticals. Two CSIC institutes participate in this initiative: the Institute of Nanoscience and Materials of Aragón (INMA, CSIC-UNIZAR) and the Institute of Materials Science of Barcelona (ICMAB, CSIC), both groups members of the CIBER-BBN. Nanomol Technologies S.L., a growing SME spin-off from ICMAB-CSIC, is also partner of the project.

PHOENIX, which is coordinated by Luxembourg Institute of Science and Technology (LIST), supported by the german SME MyBiotech in scientific coordination, will have a duration of 48 months starting on 1 March 2021 with a total budget of €14.45 million and a requested EU contribution of €11.1 million.

Open Innovation Test Bed for nano-pharmaceuticals

Nano-pharmaceuticals are drugs that use nanotechnology (the use of matter on an atomic, molecular, and supramolecular scale for industrial purposes) in some form to achieve enhanced drug products. For example, contrast agents are used in the form of nanoparticles rather than a molecule because nanoparticles are more stable and can stay longer in blood. Another example could be that a nanoparticle is used as a nanocarrier to encapsulate the drug substance and protect it while enhancing adsorption and biodistribution, or to target the drug to specific tissues or organs.

Nano-pharmaceuticals have the potential to drive the scientific and technological uplift, offering great clinical and socioeconomic benefits to society in general, industry, and patients. Nevertheless, affordable and advanced testing, manufacturing facilities and services for novel nano-pharmaceuticals are main prerequisites for successful implementation of these advances to further enhance the growth and innovation capacity.

The establishment of current good manufacturing practices (GMPs) in nano-pharmaceutical production on a large scale is the key step to successfully transferring nano-pharmaceuticals from bench to bedside (from the lab to the patients). Due to the lack of resources to implement GMP manufacturing on site, the upscaling and production of innovative nano-pharmaceuticals is still challenging to the main players of EU nanomedicine market, start-ups and SMEs. To allow a successful implementation of nano-pharmaceuticals in the nanomedicine field, there is an urgent need to establish a science and regulatory-based Open Innovation Test Bed (OITB).

PHOENIX: key project in taking nano-pharmaceuticals from bench to bedside

The PHOENIX project aims to enable the seamless, timely and cost-friendly transfer of nano-pharmaceuticals from lab bench to clinical trials by providing the necessary advanced, affordable and easily accessible PHOENIX-OITB which will offer a consolidated network of facilities, technologies, services and expertise for all the technology transfer aspects from characterisation, testing, verification up to scale up, GMP compliant manufacturing and regulatory guidance.

PHOENIX-OITB will develop and establish new facilities and upgrade existing ones to make them available to SMEs, starts-up and research laboratories for scale-up, GMP production and testing of nano-pharmaceuticals, either based on small chemical molecules or biologicals The services and expertise provided by the OITB will include production and characterisation under GMP conditions, safety evaluation, regulatory compliance and commercialisation boost.

“Our goal is to create a new infrastructure at European level available for all research centres and laboratories, SMEs and start-ups, to facilitate the transfer of nano-pharmaceuticals from the lab to the clinical practice” explains Jesús Martínez de la Fuente, INMA-CSIC-UNIZAR researcher.

“The role of INMA and ICMAB is to generate new services, open to the public, to characterize nano-pharmaceuticals in rder to ensure their quality” affirms Nora Ventosa, ICMAB-CSIC/CIBER-BBN researcher and Director of NANBIOSIS unit 6 Biomaterial Processing and Nanostructuring Unit.

Project partners

The 11 partners that form the PHOENIX consortium are the Luxembourg Institute of Science and Technology (LIST, Luxembourg), MyBiotech (SME from Germany), Nanomol Technologies SL, LeanBio SL and Grace Bio SL (SMEs from Spain), Cenya Imaging B.V. (SME from The Netherlands), BioNanoNet Forschungsgesellschaft mbH (BNN, Austria), CSIC (INMA, CSIC-UNIZAR and ICMAB, CSIC), Institute for Medical Research and Occupational Health (IMROH, Croatia), Research Center Pharmaceutical Engineering GmbH (RCPE, Austria), and Topas Therapeutics GmbH (Germany).

More information:

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In search of antimicrobials from natural bee products to coat implantable biomaterials, avoiding resistance.

The Microbial Adhesion research group-NANBIOSIS ICTS U16 Surface Characterization and Calorimetry Unit of the University of Extremadura (AM-UEX)-, belonging to the CIBER-BBN, led by Maria Luisa González, is searching in natural products, specifically in propolis, compounds with antimicrobial activity to help fight infections associated with biomaterials.

Medical devices have greatly improved healthcare. But biofilm-associated infections related to the use of these devices are a major clinical concern. Biofilms are understood as bacterial communities that adhere to the surface of the devices and are embedded in a polymeric matrix that they themselves produce. This supracellular social organization arises as a survival strategy in hostile environments, such as the human being itself, endowing the microorganisms embedded in it with resistance to mechanical clearance, the host’s immune response and antimicrobial agents. In this context, to prevent bacterial adhesion and the subsequent formation of biofilms, one of the prevention strategies is the coating of the biomaterial surfaces or the incorporation into the biomaterial itself of antimicrobial agents that can prevent their development. These type of infection are also aggravated by the multi-resistance of the microorganisms involved. For this reason, the AM-UEX group works in the search for natural products, with antimicrobial activity, that do not generate resistance, for their incorporation into new implantable biomaterials.

Bees are our allies, and their products can be a good source of available antimicrobials. Propolis is a glue for the hive and is a potentially useful food additive as it contains antioxidant and preservative properties. However, its application in other fields is limited, due to its strong flavor and low solubility. In addition, standardization is difficult because its chemical composition varies according to the flora of the environment. However, it’s common to all that they exhibit remarkable biological activities.

In a first study, the chemical composition of a Spanish propolis with a high antimicrobial capacity against bacterial strains closely related to infections associated with the formation of biofilms on biomaterials, Staphylococcus epidermidis, has been identified. The group has found in a novel Spanish ethanolic extract of propolis (SEEP) a high amount of polyphenols (205 ± 34 mg GAE / g), of which more than half correspond to the flavonoids group ( 127 ± 19 mg QE / g). The importance of this finding lies in the remarkable antioxidant and antimicrobial activities that have been attributed to this class of phenols. In addition, a more detailed analysis revealed the presence of compounds that are also present in olive oil such as vanillic acid, 1-Acetoxypinoresinol, p-HPEA-EA and 3,4-DHPEA-EDA, not previously detected in samples of propolis, which contribute to various health benefits. Other compounds found in relatively low amounts such as ferulic acid and quercetin also provide important therapeutic benefits. Regarding the antimicrobial properties of SEEP, a high sensitivity for S. epidermidis at low concentrations and a high inhibitory capacity at lower concentrations were found.

The antibacterial activity of propolis has been extensively studied, but its mechanism of action remains unclear. Research by our group has focused on measuring alterations in the physicochemical properties of the outermost surface layer of bacterial cells, both in gram-positive (S. epidermidis) and gram-negative (E. coli) cells, after incubation. with different concentrations of this antimicrobial agent. Propolis was found to induce substantial changes in bulk charge density, electrophoretic smoothness, and degree of hydrophobicity of the outermost surface layer of cells. Furthermore, observation by electron microscopy and determination of the release of cellular components carried out in NANBIOSIS Unit 16 of CIBER-BBN and UEX showed that propolis at sub-bactericidal concentrations already causes, at least locally, structural and morphological damage and/or disturbances in the cell wall. This research proposes that the mechanism of action of propolis against bacteria comes initially from the structural damage of the membrane / wall produced by the different constituents of propolis. It is a mechanism of action to which it can be difficult for bacteria to generate resistance, especially if different SEEP molecules work together synergistically.

Reference articles:

Fernández-Calderón, M. C., Navarro-Pérez, M. L., Blanco-Roca, M. T., Gómez-Navia, C., Pérez-Giraldo, C., and Vadillo-Rodríguez, V. (2020). Chemical Profile and Antibacterial Activity of a Novel Spanish Propolis with New Polyphenols also Found in Olive Oil and High Amounts of Flavonoids. Molecules 25, 3318. [DOI]

Vadillo-Rodríguez V, Cavagnola MA, Pérez-Giraldo, Fernández-Calderón MC. (2021) A physico-chemical study of the interaction of ethanolic extracts of propolis with bacterial cells. Colloids Surf B Biointerfaces 200, 111571. [DOI]

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